Parkinson's disease (PD) is the second most prevalent neurodegenerative disease and affects more than one million elderly Americans. As the population ages, the burden of PD is expected to increase. Although there are effective measures to control the symptoms of PD, patients eventually develop severe physical and mental disabilities and often die of complications. My research aims to ascertain the environmental and genetic causes of PD and to characterize high-risk populations through research on pre-motor symptoms and biomarkers. Genes and environmental factors, alone or in combination, contribute to PD development. Over years, our research has contributed to a better understanding of the role of environmental factors in Parkinson's etiology, for example, on smoking, coffee drinking, infections, and use of certain medications. In the past year, we investigated some other potential risk factors for PD. For example, previous epidemiological studies have shown that head injury may increase the risk of PD. We for the first time demonstrated in our analysis that this association was more likely due to head injury that occurred early in life (Parkinson Relat Disord, 2015). In the same publication, we also reported a potential interaction between head injury and a genetic variation. In 2015, we also examined plasma cholesterol levels in relation to PD risk (Mov Disord 2015). While higher total cholesterol is bad for cardiovascular health, our data suggest that it may be associated with a lower risk for PD. Another important area of my research is the epidemiology of pre-motor symptoms of PD. Clinicians and scientists have known for years that in addition to the characteristic motor signs, PD patients suffer from non-motor symptoms ranging from hyposmia (poor sense of smell) to dementia and psychosis. Although these symptoms can develop both before and after the clinical diagnosis of PD, I am interested in several symptoms that may develop prior to disease diagnosis by years. Examples of these symptoms include hyposmia, constipation, depression, certain sleep disturbances, and symptoms of autonomic dysfunction. These pre-motor symptoms may greatly facilitate research to identify populations at higher risk for PD and to understand early PD etiology. In the past, we have examined several individual symptoms in relation to PD risk. I am now conducting epidemiological studies to better characterize pre-motor symptoms in various populations and to understand their relevance to the natural history and etiology of PD. Our specific hypotheses are that 1) the presence of multiple pre-motor symptoms in the same individual predicts higher risk of PD; 2) environmental (e.g. smoking, caffeine intake, pesticide exposure, ibuprofen use) and genetic (e.g. SNCA, MAPT) factors affect the presence of these pre-motor symptoms and/or modify their progression to overt PD. We published 3 papers on this topic in 2015. We first conducted a meta-analysis and clearly demonstrated that these symptoms were much more prevalent in PD cases than in controls (Transl Neurodegener, 2015). Then using data from de novo PD patients and controls, we showed that a few nonmotor symptoms, poor sense of smell in particular, could efficiently differentiate PD cases from controls (Neurology, 2015). Finally, using data from a well-designed cohort study, we for the first time have demonstrated that low heart rate variability, a marker of cardiac autonomic dysfunction, was associated with a higher risk for PD (Ann Neurology, 2015). I am the principal Investigator on several PD studies that were built on large prospective cohorts. I have focused on prospective cohorts over case-control studies because they are relatively less prone to recall bias and reverse causation. Since PD is a rare outcome, large cohorts and long follow-up times are needed; research built on existing cohorts allows for relatively efficient and cost-effective case-identification. Further, by its nature, pre-motor research requires prospective studies. My ongoing projects include the Parkinson's Genes and Environment Study based on the NIH-AARP Diet and Health cohort, the PD project in the Atherosclerosis Risk In Communities study, and the Shanghai Parkinson's Study in the Shanghai Women's Health Study. Further, in collaboration with Branch colleagues, I am developing PD research in the Agricultural Health Study and the Sister Study. Finally, I have an ongoing collaboration with investigators at the Karolinska Institute. While these studies have different specific foci, they share a common theme of revealing the causes of PD and characterizing high risk populations for the purpose of disease prevention. In addition to PD research, I am also a member of the Global Burden of Disease group that estimated the public health burdens of a wide range of diseases across countries in the world. Primary findings were published in a series of papers on the Lancet.